The overall objective of this grant is an in-depth investigation of the physiology and pathophysiology of the upper esophageal sphincter (UES) motor function in health and disease. Specific objectives for this competitive renewal are to: l) Delineate further the pathophysiological basis of pharyngo-UES related dysphagic conditions. This section will include disorders of UES opening with special emphasis on differentiating between UES opening and relaxation. (a) The hypothesis that abnormal deglutitive UES opening is caused by an abnormality of one or more of the principle elements of the normal UES opening mechanism will be tested, these abnormalities include: i) abnormal deglutitive UES relaxation resulting in persistence of active cricopharyngeal tension during swallowing; ii) abnormalities of passive tension of the cricopharyngeus (CP) muscle resulting in its reduced distensibility, iii) abnormalities of the active traction on the UES during swallowing (generated by the suprahyoid muscles that when contracted induce anterior hyoid and laryngeal displacement) resulting in the diminished or absent pulling and opening force exerted on the UES, and iv) abnormalities of pulsion forces imparted to the relaxed UES by an oncoming pharyngeal bolus. Therefore, a variety of clinical conditions of abnormal UES opening will be investigated. In correlation to this topic the relative contribution of various supra- and infrahyoid muscles to the UES deglutitive opening will be studied. (b) Using the normalcy data accumulated during the last funding period, the manometric abnormalities of the deglutitive pharyngeal function in several diseases such as myopathy, radiation, metabolic-induced and primary myopathies that affect the pharyngeal muscles and may lead to dysphagia will be determined. 2) The pathophysiologic basis of age-related changes in deglutitive pharyngo-UES function detected and quantified during the last funding period will be elucidated. We will test the hypothesis that: (a) age-related pharyngo-UES motor function is associated with significant neurochemical alterations; and (b) manometric abnormalities such as increased hypopharyngeal intrabolus pressure, found in the elderly, is due to the reduced cross-sectional area of UES deglutitive opening. 3) The work on the normal physiology of swallowing will be continued, this part includes: a) studies of kinematics and dynamics of pharyngo-UES bolus transport; b) brain stem control of UES function in a feline model; and c) expansion of our preliminary work on identification of the cerebral cortical region(s) involved in swallowing in man by a noninvasive technique of functional magnetic resonance imaging. 4) Continue our work in developing a computerized mathematical model of UES opening, pharyngeal and transsphincteric bolus transit using magnetic resonance imaging techniques. Individual, but interrelated protocols are proposed to achieve our objectives and will be executed by our multidisciplinary, interdepartmental team.